title: Lead optimization of 4-acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines as A2A adenosine receptor antagonists for the treatment of Parkinson's disease.
abstract: 4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA2A receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA2A Ki 2.3 nM, hA1 Ki 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA2A Ki 0.83 nM, hA1 Ki 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA2A Ki 0.44 nM, hA1 Ki 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation of l-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, 12780 El Camino Real, San Diego, California 92130, USA.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: John E
authors.initials: JE
authors.lastname: Tellew
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Luo
authors.forename: Manisha
authors.initials: M
authors.lastname: Moorjani
authors.forename: Emily
authors.initials: E
authors.lastname: Lin
authors.forename: Marion C
authors.initials: MC
authors.lastname: Lanier
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chen
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Lechner
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Tanya
authors.initials: T
authors.lastname: Joswig
authors.forename: Robert
authors.initials: R
authors.lastname: Petroski
authors.forename: Jaime
authors.initials: J
authors.lastname: Piercey
authors.forename: William
authors.initials: W
authors.lastname: Kargo
authors.forename: Siobhan
authors.initials: S
authors.lastname: Malany
authors.forename: Mark
authors.initials: M
authors.lastname: Santos
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Gross
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Kayvon
authors.initials: K
authors.lastname: Jalali
authors.forename: Zhihong
authors.initials: Z
authors.lastname: O'Brien
authors.forename: Carol E
authors.initials: CE
authors.lastname: Stotz
authors.forename: María I
authors.initials: MI
authors.lastname: Crespo
authors.forename: José-Luis
authors.initials: JL
authors.lastname: Díaz
authors.forename: Debora H
authors.initials: DH
authors.lastname: Slee
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006220:Haloperidol; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010300:Parkinson Disease / Q000188:drug therapy*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines; D006220:Haloperidol